DESCRIPTION (Unedited Applicant's Abstract): Post-operative low cardiac output due to cardiac contractile dysfunction after open-heart surgery, is frequently treated with moderate to high dose inotropic drugs to maintain adequate cardiac output. In children this is especially true due to the limited availability of mechanical circulatory support. We have shown that cytosolic calcium is significantly elevated in the post-ischemic heart in association with higher oxygen consumption and catecholamine type motropic drugs further raise intracellular calcium. There is the potential, therefore, for marked and sustained elevation of cytosolic calcium post ischemia, the end result of which may be irreversible myocyte injury with necrosis and/or apoptosis. The effects of this type of damage are likely to have important consequences for long-term cardiac function, particularly in pediatric cardiac surgery where multiple cardiac procedures are frequently required for correction of congenital defects. The cumulative myocardial damage in addition to the abnormal work loads imposed on the myocardium from the anatomic defects may in part be responsible for the growing number of adult patients seen with contractile dysfunction late after repair of congenital defects. Based on our results, we hypothesize that the sustained elevation of cytosolic calcium leads to mitochondnal calcium accumulation. Calcium loading of mitochondria and the conditions present post-ischemia result in myocyte death fror mitochondrial disruption, or from opening of the mitochondrial permeability transition pore with release of pro-apoptoti factors from the intermembrane space. We also postulate that by preventing the marked rise in cytosolic calcium post ischemia or altering the conditions under which mitochondrial calcium loading occurs, we can significantly reduce myocyte death from necrosis and/or apoptosis in the catecholamine treated post-ischemic heart. Using a model of heterotopic transplanted working heart in genetically inbred rabbits; we will pursue three specific aims to: I. Determine the time course and dose dependence of reperfusion and catecholamine mediated myocyte damage, II. Determine whether sustained adrenergic stimulation and elevated cytosolic calcium post-ischemia lead to mitochondrial dysfunction via opening of the permeability transition, promoting apoptosis and/or necrosis, and III. Evaluate the efficacy of interventions to prevent mitochondrial dysfunction on post-ischemic myocardial recovery. Understanding of the mechanism of myocyte damage generated by ischemia/reperfusion and adrenergic drugs will Permit us to develop treatments to prevent this injury.